Patient perspective on decisions to switch disease-modifying treatments in relapsing-remitting multiple sclerosis.

BACKGROUND: There are now large cohorts of people with relapsing-remitting multiple sclerosis (pwRRMS) who have taken several Disease-Modifying Treatments (DMTs). Studies about switching DMTs mostly focus on clinical outcomes rather than patients' decision-making. Neurologists are now required to support decisions at various times during the relapsing disease course and they do so with concerns about DMTs risks. This qualitative study investigates how pwRRMS weigh up the pros and cons of DMTs, focusing on perceptions of effectiveness and risks when new treatments are considered. OBJECTIVE: To increase understanding of people's experiences of decision-making when switching DMTs. METHODS: 30 semi-structured interviews were conducted with pwRRMS in England. 16 participants had switched DMT and their experiences were compared with those who had only taken one DMT. Interviews were analysed thematically to answer: what main factors influence people's decision-making to switch DMTs and why? RESULTS: Of the 16 participants with experience of switching DMT, eight had taken two or more DMTs; eight had taken three or more. Two was the DMT median. This study demonstrated that despite the term "switching" implying that similar treatments are inter-changeable, for pwRRMS taking new treatments involves different emotions, routines, risks, prognosis and communication experiences. Two meta themes identified were: 1) A distinctive, rapid and emotional decision-making process where old emotions related to MS prognosis are revisited. 2) Switching has a different impact on communication for escalation or de-escalation processes. CONCLUSION: Switching DMT involves different routines, risks, prognosis and communication experiences. These decisions are emotionally difficult because of the fear about transitioning to secondary progressive MS, and DMT effectiveness uncertainty. Patient centred decision aids should include information about first and consecutive treatment decisions.

Nonsteroidal anti-inflammatory drugs: new perspectives on a familiar drug class.

Nonsteroidal anti-inflammatory drugs are among the most commonly used and lethal drug classes. The anti-inflammatory, analgesic, and antipyretic effects result from the inhibition of cyclooxygenase (COX), which is the critical enzyme in the synthesis of prostaglandins. The most common adverse effects are gastrointestinal, but renal and platelet effects are also important. Recent discovery that there are two forms of cyclooxygenase (COX-1 and COX-2) has led to hypothesis that the newly marketed COX-2 selective inhibitor can provide beneficial effects without these adverse effects. Patient monitoring and education are nursing functions essential to the safe use of these agents.

Pharmacology of antihypertensive drugs.

The wide variety of first-line agents available for managing high blood pressure include diuretics, beta adrenergic receptor blockers, alpha adrenergic receptor blockers, angiotensin converting enzyme inhibitors, and calcium channel blockers. Supplemental agents used for second-line therapy and special indications, such as pregnancy and hypertensive emergencies, include angiotensin receptor blockers, central-acting agents, direct vasodilators, and adrenergic neuron inhibitors. Selection of agents for particular patients requires consideration of research-based evidence for positive long-term outcomes and of the unique patient profile of age, race, co-morbidities, and lifestyle. A thorough understanding of the pharmacology (mechanism, pharmacokinetics, adverse effects and drug interactions, clinical use) of antihypertensive agents is an essential foundation for nursing practice in women's health.

Sympathetic activation in heart failure and its treatment with beta-blockade.

Multiple models explaining the pathogenesis of heart failure have been put forth during the past 5 decades. These models were modified as clinical evidence supported or refuted their assumptions. During the past 2 decades, heart failure models emphasized the importance of neurohormonal systems in heart failure progression. The positive impact that angiotensin-converting enzyme inhibitors have had on mortality from heart failure has bolstered the neurohormonal theory. Attention recently has turned to the sympathetic nervous system and its potential deleterious effects on the cardiovascular system in heart failure. The sympathetic nervous system can negatively impact the cardiovascular system in heart failure in several ways, including down-regulating beta1-receptors, exerting direct toxic effects on the myocardium, and contributing to myocardial remodeling and life-threatening arrhythmias. Beta-adrenergic blockers have shown promise for reducing morbidity and mortality in heart failure, but definitive reductions in mortality remain to be shown by future investigations.

Essential hypertension: could the basic defect be in blood supply of vasomotor centre?

Various factors have been implicated in the pathogenesis of essential hypertension, although the exact cause of essential hypertension is still unknown. In this paper it is suggested that the basic pathology in essential hypertension may be an inherited defect in the blood supply of that part of reticular formation of rostral ventrolateral medulla which contains the pressor area. The posited defect is one in which the arterial branch supplying blood to the above-mentioned pressor area of vasomotor center arises from an artery which is stenosed. The other branches of this stenosed artery supply adjacent areas of medullary reticular formation concerned with other neurological functions. Due to this stenosis there is ischaemia of the pressor area resulting in increased systemic arterial pressure. During stress, the blood requirement of adjacent areas of the reticular formation (whose function is still not clearly defined) may increase, thus further decreasing blood flow to vasopressor area and increasing the cerebral ischaemic response. After a prolonged time, this increased blood pressure can cause hyaline arteriolar nephrosclerosis in kidney, which may participate in the maintenance of elevated systemic arterial pressure.

Adrenal insufficiency occurring during septic shock: incidence, outcome, and relationship to peripheral cytokine levels.

PURPOSE: In patients with septic shock, to (1) determine the incidence of adrenal insufficiency (AI), (2) observe the effects of glucocorticoid therapy on outcome in those with impaired adrenal function, and (3) investigate a possible correlation between adrenal function and peripheral cytokine levels. PATIENTS AND METHODS: Twenty-one patients admitted to the medical and surgical intensive care unit with septic shock and 11 healthy volunteers were studied. Cortisol, tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) levels were measured before and after infusion of low (1 microgram) and standard doses (250 micrograms) of adrenocorticotropic hormone (ACTH) within 24 hours of the diagnosis of septic shock. Patients with subnormal adrenal responses to ACTH were treated with stress doses of steroids. Hormone, cytokine, and survival data in patients with normal response were compared to those with subnormal adrenal function. RESULTS: Five patients (23.8%) exhibited AI by ACTH stimulation testing. Three of them received steroid supplementation with rapid improvement in hemodynamic parameters. Autopsies of 2 patients with AI revealed intact adrenal cortices. Sixteen patients had adequate adrenal responses (AAR) to the standard-dose ACTH infusion. TNF-alpha levels were inversely correlated with mean arterial pressure (MAP) (r = -.52, P = 0.038) in AAR but not AI. There was no difference in mean peripheral TNF-alpha levels between AAR and AI. There was no correlation between TNF-alpha levels and mortality or adrenal function in those with septic shock. A trend toward lower IL-6 levels in AI suggests a link between reduced IL-6 levels and understimulation of the pituitary-adrenal axis in this group. Mortality in patients with AI was 80% at 4 weeks as compared with 43.8% in the group with normal adrenal response. CONCLUSIONS: Adrenal hyporesponsiveness is a feature of septic shock in some patients. Its etiology is probably complex. Steroid supplementation appeared to improve short-term survival when AI occurred, although these patients' overall mortality was worse than that of patients with septic shock and AAR. The standard-dose (250 micrograms) rapid ACTH infusion test was adequate for detecting AI. Adrenal insufficiency should be suspected in patients with septic shock who do not respond to conventional treatment. Performing the ACTH infusion test and initiating a trial of stress doses of glucocorticoids pending the results is a reasonable strategy in this situation.

The biologic activity of ACTH and related peptides on peripheral blood mononuclear cells is altered by the presence of dexamethasone.

We wished to determine whether the glucocorticoid hormone dexamethasone (dex), a potent modular of both pituitary-adrenal and immunologic activity, altered the effect of adrenocorticotropin-related peptides on activated peripheral blood mononuclear cells (PBMCs) and T-cells. PBMCs preactivated with Concanavalin A (Con A) and T-cells preactivated with phorbol 12,13 dibutyrate (PDB) plus phytohemagglutinin (PHA) were exposed to dex, ACTH, and related peptide sequences. Proliferation of cells was measured as was IL-2 in conditioned media. It was found that in the absence of dex only the peptide ACTH(18-39) altered proliferation of PBMCs while there was no effect of peptide on T-cells activated via protein kinase C-mediated pathways. Significant reversal of the inhibitory effect of dex on proliferation of PBMCs exposed to Con A was achieved with addition of ACTH(1-39) and ACTH(11-24), while IL-2 levels were unaffected by the addition of peptide. ACTH(18-39) and ACTH(11-24) enhanced the inhibitory effect of dex on T-cells activated with PDB plus PHA. These findings suggest that the biologic activity of ACTH on immune cells is altered when dexamethasone is present and under certain circumstances ACTH may protect the immunologic response from the inhibitory effects of elevated ambient glucocorticoids.

Alteration of serum pituitary hormone levels in postmenopausal women with stroke.

BACKGROUND AND PURPOSE: The aim of this study was to determine if circulating levels of pituitary hormones are altered by stroke and, if so, whether these alterations offer insight into specific neurochemical pathways in the region of the central nervous system injury. METHODS: Twenty-eight consecutive postmenopausal women undergoing computed tomographic imaging of the brain for evaluation of clinical evidence of stroke underwent blood sampling for determination of serum levels of luteinizing hormone, follicle-stimulating hormone, thyroid-stimulating hormone, triiodothyronine, prolactin, estradiol, and sex hormone--binding globulin. RESULTS: In stroke involving the caudate, serum levels of luteinizing hormone and follicle-stimulating hormone were reduced to 16% and 24% of concentrations found in those with stroke outside of the basal ganglia (p < 0.03 and p < 0.01, respectively). Levels of estradiol, sex hormone-binding globulin, thyroid-stimulating hormone, and prolactin were similar in all stroke groups. Nonspecific biochemical effects of stress that might influence hormone concentrations were assessed by measurement of serum triiodothyronine, the level of which is a sensitive biochemical correlate of disease severity. These levels were not different between stroke groups. CONCLUSIONS: Stroke involving the caudate nucleus may interrupt neurotransmitter pathways involved in control of secretion of gonadotropins. Peripheral levels of these hormones may serve as a marker for central neurochemical disturbances associated with stroke in specific brain regions.

Evaluation of a computer program for teaching laboratory diagnosis of acid-base disorders.

A computer program was evaluated as a tool for increasing the diagnostic acumen of medical housestaff and students in identifying acid-base disorders. The participants were randomized into two groups; group A (N = 20) was encouraged to use the software, and group B (N = 19) was denied access. Pre- and post-tests were administered to delineate the groups' ability to identify correctly an acid-base disorder from laboratory data (electrolytes and arterial blood gas). During 6 weeks, group A used the computer for a mean of 2.83 h (range 1 to 6). The mean +/- SE number of correct answers out of 20 questions, prior to use of the computer program, were 5.7 +/- 0.8 (95% confidence interval 3.9 to 7.5) for group A and 5.2 +/- 0.6 (95% confidence interval 3.9 to 6.5) for group B. These results were not statistically different. Correct responses increased significantly in group A to 10.3 +/- 0.9 (P < 0.0001, 95% confidence interval 8.4 to 12.2) but did not increase significantly in group B. The data suggest that this software program was effective in increasing the diagnostic capabilities of medical housestaff and students for identifying acid-base disorders.

The effects of a dopamine antagonist on luteinizing hormone and prolactin release in women with anorexia nervosa and in normal controls.

To evaluate the possible role of central dopaminergic suppression of gonadotropin secretion in the genesis of amenorrhea associated with anorexia nervosa (A.N.), a central D-2 dopamine receptor blocker was administered to 10 women with A.N. and 10 regularly menstruating age-matched controls. Serum prolactin and luteinizing hormone (LH) levels were measured at -15, 0, 30, 60, 120, and 180 min after administration of metoclopramide (10 mg orally). Mean basal prolactin (p less than 0.001) and estradiol levels (p less than 0.02) were significantly lower in women with A.N. The prolactin response to metoclopramide was significantly impaired in women with anorexia nervosa. No correlation was found between the prolactin response and percentage ideal body weight. Basal and post-stimulation prolactin levels were correlated with estradiol levels. After adjusting for the effects of estradiol, significant differences between patients with A.N. and controls remained in prolactin levels at baseline (p less than 0.01), 120 min (p less than 0.02) and 180 min (p less than 0.05). Metoclopramide did not induce a significant rise in LH levels in either the A.N. or control groups. These data are consistent with central dopaminergic inhibition of prolactin secretion in anorexia nervosa but do not support the hypothesis that central dopaminergic inhibition is related to diminished LH release in this state.

Adrenocortical insufficiency with normal serum cortisol levels and hyporeninaemia in a patient with acquired immunodeficiency syndrome (AIDS).

The acquired immunodeficiency syndrome (AIDS) has been associated with abnormalities of adrenocortical function, and hypoaldosteronism due to hyporeninaemic hypoaldosteronism (HHA). We here report the case of a woman with AIDS associated with orthostatic hypotension, persistent hyponatraemia and hyperkalaemia, in whom basal serum cortisol levels were normal and serum renin activity was low. Subsequent post-mortem examination revealed almost complete adrenocortical destruction. A possible explanation of this apparently contradictory combination of findings is discussed, together with the therapeutic implications for similar cases.

Quantification and characterization of ACTH-related peptides produced by human peripheral blood mononuclear cells.

We have used a sensitive radioimmunoassay to quantify and characterize PBMC-associated immunoreactive ACTH (ACTH-IR). Mean ACTH content of freshly isolated human PBMCs was 3.8 +/- 0.72 pg (SEM) per 10(6) cells. During 3 days of incubation ACTH-IR in conditioned media of control PBMCs increased significantly, p less than 0.02. Gel filtration chromatography revealed a minor peak of ACTH-IR coeluting with ACTH (1-39) and a major peak coeluting with ACTH (11-24). Treatment with 15 nM CRH did not alter the amount of ACTH-IR secreted or its gel pattern. Synthetic ACTH (11-24), was radioiodinated and was used for binding experiments that demonstrated specific high- and low-affinity binding sites for ACTH (11-24) on a human T cell line. These results add support for a role of ACTH and related peptides in immune regulatory systems and suggest that cell-specific post-translational processing of POMC may generate an expanding number of biologically active moieties.

Ketoconazole use in the treatment of ovarian hyperandrogenism.

Ovarian hyperandrogenism is a common disorder of women of reproductive age. The therapies that are presently available to treat this disorder are not uniformly effective or free of adverse effects. We conducted a prospective study of eight women receiving ketoconazole for a mean duration of 44 +/- 15 (SEM) weeks, as therapy of ovarian hyperandrogenism. Serum testosterone and hair growth rate declined in patients while on 600 to 1,000 mg ketoconazole daily. Menses normalized in seven of eight subjects during treatment. Ketoconazole therapy was not associated with a change in basal or postgonadotropin-releasing hormone stimulation gonadotropin levels. Basal cortisol levels were also unchanged on ketoconazole though responsiveness of cortisol to adrenocorticotropic hormone stimulation tended to be reduced. We conclude that ketoconazole can effectively reverse the biochemical and clinical abnormalities of ovarian hyperandrogenism. Until the issue of its safety is resolved, ketoconazole therapy is best limited to select individuals who agree to careful monitoring and the use of reliable birth control methods during treatment.

Fine-needle aspiration biopsy of the thyroid nodule. Results of a start-up project in a general teaching hospital setting.

The results of the initial 102 fine-needle aspiration biopsies of the thyroid performed at a 795-bed general teaching hospital are reported. Eighty-four of the nodules (82%) were cytologically benign, 18 nodules (18%) were suspicious, and none of the nodules was diagnosed as malignant. Five nodules In the suspicious group (28%) were found to be malignant following microscopic examination of the surgical specimens. There was one false-negative result. Based on the data from 21 patients with both cytologic and histologic diagnoses, the positive predictive value of this procedure was 38% and the negative predictive value was 87% (sensitivity, 83%; specificity, 47%). Our results were comparable with those of major referral centers. Guidelines for establishing a fine-needle aspiration biopsy program at a general hospital are suggested.